ISOThrive, Inc.

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted between June 26 and June 30, 2023. Investigator Rebecca T. Davis, representing FDA, reviewed the role of ISOThrive, Inc. (ISOThrive) as the sponsor of the following clinical investigations of the investigational drug (b)(4):

(b)(4)

(b)(4)

This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected.

At the conclusion of the inspection, Investigator Davis presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your July 20, 2023, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated July 20, 2023, it appears that ISOThrive did not adhere to the applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in Title 21 of the Code of Federal Regulations, part 312 (21 CFR 312) governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:

You failed to submit an Investigational New Drug application (IND) for the conduct of clinical investigations with an investigational new drug that is subject to 21 CFR 312.2(a) [21 CFR 312.20(a), 312.20(b), and 312.40(a)].

FDA regulations require a sponsor to submit, and to have in effect, an IND before initiating a clinical investigation of a drug that is subject to 21 CFR 312.2(a) [see 21 CFR 312.20 and 312.40(a)] in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2. ISOThrive failed to comply with these requirements. Specifically, ISOThrive initiated and conducted the following clinical investigations of an investigational drug subject to section 505 of the FD&C Act [21 U.S.C. 355] without submitting and having in effect an IND:

The clinical investigation of the investigational drug (b)(4) conducted under Protocol (b)(4)

The clinical investigation of the investigational drug (b)(4) conducted under Protocol (b)(4)

In your July 20, 2023, written response to the Form FDA 483, ISOThrive stated that after review of the FDA regulations and guidance1, it determined that Protocols (b)(4) and (b)(4) were IND-exempt for the following reasons: (1) The investigational drug, (b)(4), was and remains a commercially available dietary supplement; (2) the endpoint of both studies was tolerability of the product; and (3) neither of these studies was designed with an “intent-to-treat” a disease. Additionally, ISOThrive stated that in October 2022, an IND application was submitted to FDA once it was desired to study the investigational drug as a potential treatment option for a specific disease.

However, Protocols (b)(4) and (b)(4) do not qualify for any of the exemptions listed at 21 CFR 312.2 from the application of 21 CFR 312. To be IND-exempt under 21 CFR 312.2, the investigational product must be lawfully marketed in the United States as a drug product. As explained in your July 20, 2023, written response, (b)(4) is marketed as a dietary supplement, not as a drug product.

For the reasons described below, we conclude that the evidence collected during the inspection shows that (b)(4) was intended for use as a drug, not as a dietary supplement, in the two clinical investigations named above. Therefore, ISOThrive was required to submit an IND before conducting the clinical investigations.

Section 201(g)(1) of the FD&C Act [21 U.S.C. 321(g)(1)] defines a drug as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals….” ISOThrive studied the effectiveness of (b)(4) for treating a disease, as described below:

Although Protocol (b)(4) identified the “efficacy endpoint” as an assessment of tolerability of (b)(4) in subjects with (b)(4), the “primary outcome measures” for Protocol (b)(4) included measurement of differences in baseline and post-intervention scores of (b)(4) (for example, symptoms of (b)(4)) on the (b)(4) ReQuest Short Version and (b)(4) ReQuest Long Version questionnaires in subjects with (b)(4). These instruments are used to assess (b)(4), including symptoms of (b)(4). Therefore, Protocol (b)(4) collected study data to assess the effect of (b)(4) on (b)(4), as measured by (b)(4).

Although Protocol (b)(4) identified the ”efficacy endpoint” as an assessment of tolerability of (b)(4) in subjects with (b)(4), the “primary outcome measures” for Protocol (b)(4) included differences in baseline and post-intervention scores on various questionnaires that are used to assess symptoms of (b)(4), including changes in bowel movement frequency and quality, in subjects with (b)(4). Therefore, Protocol (b)(4) collected study data to assess the effect of (b)(4) on (b)(4), as measured by (b)(4).

Whether an investigational article is a drug or a dietary supplement depends on the intent of the investigation. Based on the study designs of Protocols (b)(4) and (b)(4), the investigational product, (b)(4), as used in these clinical investigations, was a drug as defined in section 201(g)(1) of the FD&C Act because (b)(4) was studied for use in the treatment of (b)(4) and for use In the treatment of (b)(4), respectively.

Thus, before initiating the clinical investigations of (b)(4) conducted under Protocols (b)(4) and (b)(4), under 21 CFR 312.40 ISOThrive was required to submit an IND to FDA and to have an IND in effect. FDA’s records indicate that ISOThrive failed to submit an IND before conducting Protocol (b)(4), in which 176 human subjects were enrolled and received study drug between July 15, 2020, and July 10, 2021; and before conducting Protocol (b)(4), in which 112 human subjects were enrolled and received study drug between November 17, 2020, and March 5, 2021.

We acknowledge your statements in your written response that you would “enhance [your] procedures for determining when an IND is required, thus allowing [your] future decisions to more closely align with the agency’s requirements and expectations.” However, your written response to the Form FDA 483 did not provide sufficient details of ISOThrive’s corrective action plan for developing and implementing procedures to comply with IND regulations, moving forward. As a result, ISOThrive’s response is inadequate. Without this information, we are unable to determine whether ISOThrive will comply with IND regulations in the future.

As a sponsor, you are responsible for ISOThrive’s compliance with IND requirements, including submitting and having in effect an IND before initiating a clinical investigation, and it is your responsibility to be aware of and to follow all applicable FDA regulations. ISOThrive’s failure to submit, and to have in effect, an IND before initiating clinical investigations with an investigational drug raises significant concerns regarding the safety and welfare of enrolled subjects, and raises concerns about the validity and integrity of data collected during the conduct of these clinical investigations.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical studies of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address any deficiencies and establish procedures to ensure that any ongoing or future studies comply with FDA regulations.

This letter notifies you of our findings and provides you with an opportunity to address the deficiencies noted above. Within 15 business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to address this matter adequately may lead to regulatory action. If you believe you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.

Should you have any questions or concerns regarding this letter or the inspection, please email FDA at CDER-OSI-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:

Brittany L. Garr-Colón, M.P.H.Branch ChiefCompliance Enforcement BranchDivision of Enforcement and Postmarketing SafetyOffice of Scientific InvestigationsOffice of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug AdministrationBuilding 51, Room 535210903 New Hampshire AvenueSilver Spring, MD 20993